Costs of UK community care for individuals with recessive dystrophic epidermolysis bullosa: Findings of the Prospective Epidermolysis Bullosa Longitudinal Evaluation Study

Abstract Background Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin fragility disorder requiring multidisciplinary management. Information regarding costs of current standard treatment is scant. Objectives As part of a longitudinal natural history study, we explored the community care costs of UK patients with different forms of RDEB. Methods Fifty‐nine individuals with RDEB provided detailed information on multiple facets of RDEB including disease severity scores (iscorEB, BEBS) and patient reported outcomes (quality of life evaluation in epidermolysis bullosa, iscorEB patient questionnaire). Costs data included time spent doing dressings, frequency of dressing changes, details of materials used, and paid and unpaid care. Results Overall costs of dressing materials and associated care were high in RDEB. Median annual costs across all subtypes for those using dressings (n = 51) were over £26 000. For severe RDEB (RDEB‐S), median costs were almost £90 000 per annum, with a median of 18 h per week spent on dressing changes. Half of working‐age adults with RDEB were unemployed and 39% of carers were unable to take on full‐time or part‐time paid employment, adding to indirect costs and the financial burden from RDEB on families and society. Conclusions The findings demonstrate the high costs of care of RDEB, particularly for RDEB‐S. The current expense supports the drive to develop new therapies which accelerate wound healing and diminish total wound burden, thereby reducing costs of dressings and care. While costly to bring to market, these might ultimately reduce the overall cost of treatment and also the impact on individuals living with this rare disease. The data also highlight the need for adequate reimbursement for EB care which can place significant financial strain on families.

Epidermolysis bullosa comprises a group of rare inherited mucocutaneous fragility disorders.The overall prevalence per million population in the Netherlands 1 and UK2 in 2020 was 22.4-34.8compared with an estimated 11.1 prevalence in the USA in 2002. 3Reported UK prevalence of recessive dystrophic EB (RDEB) ranges from 1.4 to 3.3 per million, with incidence between 3.05 and 8.1 per million live births. 2 Skin erosions and chronic wounds are common and may be extensive requiring expensive specialised dressings which can be time-consuming to change.In RDEB, particularly the severe form, RDEB-S, extracutaneous complications are frequent and lifespan can be significantly foreshortened, 4,5 notably from aggressive cutaneous squamous cell carcinomas developing in early adult life. 6,7Management of EB is multidisciplinary and intensive, by necessity, associated with high healthcare and resource use costs, 8 including direct medical costs (dressings, medications, hospital appointments, procedures), direct non-medical costs (paid care), and indirect costs (productivity losses from patients and family members unable to undertake paid employment due to care needs). 9are or 'orphan' disorders such as EB previously attracted little attention from biopharmaceutical companies; developing and bringing new therapies to market was considered financially unviable while benefitting relatively few individuals.However, arguments for developing new therapies for rare diseases may be more complex than a straight cost/benefit analysis. 10][13][14][15] Costs of illness studies are important in defining healthcare and research priorities for governments and biopharmaceutical companies. 16However, such studies in rare diseases, including EB, are scant. 17,18A questionnaire-based study in 8 European countries in 2016 reported average annual care costs of €31,390 for all EB types. 8Further analysis of the same data in 2022 revealed an average care cost of €53,359 for 91 individuals with DEB from 5 European countries, including the UK, 9 although they did not stratify by DEB subtype or include costs of wound care materials.There is international consensus regarding EB care although resourcing of that care varies according to the healthcare funding system in individual nations.For example, UK healthcare is provided by the National Health Service (NHS), funded through general taxation and National Insurance contributions; patients do not directly pay for treatment except contributions (annual maximum of £112 (GBP, 2023)) towards prescription items such as wound dressings, medications, dental care.High-cost rare diseases, including EB, are funded from ring-fenced centralised NHS monies and provided by a limited number of designated Highly Specialised Services.
Ascertaining accurate data regarding full costs of care in EB is essential to ensure adequate budgeting and remuneration by national healthcare providers and/or insurers, and for biopharmaceutical companies and regulatory bodies when considering development of new therapies.Our study explores UK community care costs for different RDEB subtypes in significant depth, including the first detailed costs of wound care materials.

| Cost of care data
To capture 'real world' healthcare and resource use costs, participants and carers were asked about types and quantities of materials used during an average week, including wound care materials (dressings, topical treatments such as wound gel, reusable retention garments/tubular bandages), skin care and hygiene products (prescribed ointments, bath additives, moisturising creams), paid and informal (unpaid) carer time.These community care costs associated with delivering EB care at home are mostly funded by the NHS with some paid carers funded through social care provided by their local council (local government).In addition, the adult EB service provided clinical nurse specialist (EB-CNS) home visits whereas children were typically seen in the hospital.Community care costs are reported as British Pounds (GBP, £ or £1000s) per annum, with individual costs calculated using NHS unit costs for 2020 [19][20][21] ; preferred skin care items purchased by the participant, such as shower gel and moisturizers from the supermarket, were excluded from the analysis as not a cost to the NHS.All paid care was calculated at £12.50 per hour (average band 3 nurse NHS rate, 2020), 22 with informal care for dressing changes valued as if provided by a professional carer. 23EB-CNS costs were calculated by the hospital as £478 per visit.

| Severity scores
Disease severity was scored using 2 validated questionnaires: instrument for scoring clinical outcomes of research for EB (iscorEB) (maximum clinician score of 138, self-reported score of 120) 24 and Birmingham EB Severity Score (BEBS) (maximum score of 100). 25gher scores indicated greater RDEB activity/severity.We separately report skin wounding components as indicators of severity: BEBS reports percentage damaged skin including blisters, erosions, healing skin, erythema, atrophic scarring; iscorEB reports a composite score comprising intact skin, erosions, crusting/ scabbing, chronic wounds (>6 weeks), infection and percentage body surface area affected.Financial impact of living with EB was assessed using quality of life evaluation in epidermolysis bullosa (QOLEB) questionnaire, item 3. 26

| Statistical analysis
To provide a snapshot of costs for all RDEB and by subtype, findings are presented for (1) the index visit (first available review with complete costs data) and ( 2) an average of per-participant costs from all available reviews.Categorical variables are reported as counts and percentages, with continuous variables summarised using medians and inter-quartile range [IQR].Correlations were computed using Spearman's rank correlation.All analyses were performed using R (version 4.1.3).
Six participants had incomplete index reviews with missing iscorEB data: two children and one adult with RDEB-S, three adults with intermediate RDEB (RDEB-I).Also, one participant was missing the number of EB-CNS visits.Data for the sole participant with pretibial RDEB (RDEB-PT) (5 reviews) were included only in overall analysis.Missing-ness of data are reported where relevant in the tables and figures.

| Total cost of community care
The median annual per person cost of all RDEB community care at index review was £14 124 [1722; 87 937], including all wound care materials, skin care, paid and proportionate unpaid care, and EB-CNS home visits (Table 2).Substantially higher costs were  1a).Consideration of all reviews reporting regular dressing changes (n = 292) suggests the annual cost per person could be higher at £33 628 [5738;101 271] (Figure 1b).Data for Figures 1a and 1b are reported in Tables S3 and S4, respectively.
There were minimal or no community care costs for reviews where participants with RDEB-I or RDEB-Inv reported infrequent/no dressing changes, although some reported occasional small use of wound care materials.These participants had £0 [0;0] costs at index review, whereas, when considering all reviews, the annual costs were £107 [48;571] for those reporting infrequent dressing changes (n = 13) and just £14 [0;67] for those reporting no dressings (n = 25).

| Cost of wound care products
Table 3 shows the variation in use of wound care products, reporting the number using each treatment component and user median annual costs at index review (n = 59).Some participants used multiple care components whereas others reported only one or two products.Individuals with RDEB-S and RDEB-Pru Total paid and unpaid care 0 [0 F I G U R E 1 (a) Median annual costs for those reporting frequent dressing changes at index review (n = 51).RDEB severe (RDEB-S), intermediate (RDEB-I), inversa (RDEB-Inv), pretibial (RDEB-PT), pruriginosa (RDEB-Pru).Prices as at August 2020.RDEB-PT (n = 1) is included in RDEB-ALL costs only.See Table S3 for dataset used in Figure 1a.(b) Median annual costs for those reporting frequent dressing changes, all reviews (n = 292).Prices as at August 2020.RDEB-PT (n = 1) is included in RDEB-ALL costs only.See Table S4 for dataset used in Figure 1b.
reported the greatest wound dressing costs, £77 154 [21 891; 104 140] and £32 686 [32 322; 310 005], respectively.However, it should be noted that 1 of the 3 participants with RDEB-Pru had unusually high dressing materials costs due to extensive wounding, a large body size, and a personal preference for frequent changes and applying dressings to protect intact skin.This did not affect median costs at index review but is reflected in the IQR.Individuals with RDEB-I reported little usage and low costs, with 5 of the 9 individuals with RDEB-Inv reporting no wound dressings.Similar usage and annual costs were found when considering all available reviews (n = 330) (Table S5).
Costs were generally lower in young children where wound sizes were proportionally smaller requiring fewer items per product.Figures 2a and 2b show these median costs by age group for each subtype, with data reported in Table S6.

| Cost of carers
Only 13 participants reported paid care, with a median 15 [13;43] hours per week at index review and annual user costs of £9750 [8450; 27 950] (Table 3).The overall annual user cost for paid care was higher when considering all reviews, £18 200 [5200; 31 200], with variation between subtype; individuals with RDEB-S and RDEB-Inv had higher user costs than reported at index review whereas those with RDEB-I and RDEB-Pru had lower user costs (see Table S5).
Paid care was mostly reported by individuals with RDEB-S and RDEB-Pru.A single user with RDEB-Pru reported the greatest usage (112 h per week), with extensive wounding requiring complex and timeconsuming daily dressing changes by 2 carers; this was considered atypical as the other 2 participants with RDEB-Pru were self-caring although one received some unpaid care.There were insufficient data to determine whether paid care increased with age.
Most participants (n = 46,78%) did not use paid care, although half (n = 31,53%) received unpaid care for wound dressing changes, of whom 9 were partly selfcaring and 8 also received paid care.Proportionate annual unpaid carer costs were calculated for the 14 participants (24%) reporting only unpaid carers at index review, a median £11 565 [7394; 15 776] per person (Table 3), with similar proportionate annual unpaid carer costs found when considering all reviews (Table S5).S6 for dataset used in Figure 2. Prices as at August 2020.(b) Annual wound dressing costs reported for regular users by subtype and age group, per 1000s GBP, considering all reviews (n = 292).Subtypes RDEB-Inv and RDEB-Pru did not include children.RDEB-PT (n = 1) is included in RDEB-ALL costs only.See Table S6 for dataset used in Figure 2.
The variation in data collection methods and models for funding healthcare makes any meaningful comparisons between study findings difficult.A European multinational questionnaire-based study demonstrated significantly higher average annual costs for DEB (€53,359) compared with all forms of EB (€31,390) but did not separately report costs for RDEB. 8,9Also, that study did not include costs of dressing materials although reported direct medical costs (e.g.hospital admissions and appointments) and indirect costs, including lost income from being unable to work, which we did not.A small Irish study reported combined costs of wound care materials and medications for 4 children with RDEB (from €5986 to €89,780), and hospital admissions and clinic visits, but did not include paid and unpaid carer time. 27A recent 2022 study from the United States used data from health records and insurance claims for medical and home care (including wound dressing materials, pharmacy) for 26 patients with RDEB (subtypes unspecified) and calculated average annual care costs of $29,995 28 ; however, although bandage costs ($5341) and home nursing and wound care materials ($7615) were included, the cost of wound care materials not reimbursed by their insurers is unknown so it is not possible to determine the total cost of paid care or wound dressings.A separate United States online survey of EB patients and their carers found that more than 25% spent over $1000 per month on wound care supplies to supplement those covered by health insurance and almost 75% of families with severe EB experienced a major or moderate financial impact. 29 strength of our study is the inclusion of RDEB subtypes, adults and children, who have contributed many reviews over several years.Limitations which can make interpretation problematic include the small sample size and underrepresentation of paediatric participants and those with less common RDEB subtypes, including skewing of RDEB-Pru data by one participant; this should improve with recruitment of additional PEBLES participants.Our results assume steady use of dressings and care over the preceding 6 or 12 months since previous review such that fluctuations in weather or other factors do not influence costs incurred in care.Also, our findings underrepresent informal care and do not include other relevant healthcare costs (hospital care, investigations, medicines).

| CONCLUSIONS
This study demonstrates the very considerable costs of community care for RDEB, underscoring the particularly high costs for more severe forms of RDEB, notably RDEB-S.It comprehensively details community care costs in different RDEB subtypes, including paid and proportionate unpaid carer costs, and highlights the many hours per week spent undertaking dressing changes which contributes to the considerable burden and financial impact reported by affected families, including reduced ability of carers and individuals with EB to undertake paid work.This information supports the need for individuals with EB and their carers to have adequate provision of community care, including reimbursement of dressing materials and skincare products.The study findings also support the health economic case for developing new therapies for RDEB which might accelerate wound healing, diminish total wound burden, and thereby reduce costs of dressings and care.

3. 1 . 3 | 2
Cost of specialist nursing careMost individuals with RDEB-S (n = 17,68%) and RDEB-Pru (n = 2,67%) received a home visit from an EB-CNS in the 12-month prior to their index review, T A B L E 3 Annual usage of wound care products, paid and unpaid care, and EB-CNS support at index review (n = 59), with median user costs for each item reported in 1000s (GBP).(a) Annual wound dressing costs reported at index review for regular users (n = 51) by subtype and age group, per 1000s GBP.Subtypes RDEB = Inv and RDEB = Pru did not include children.RDEB-PT (n = 1) is included in RDEB = ALL costs only.See Table

What is already known about this topic?
Participant characteristics by recessive dystrophic epidermolysis bullosa (RDEB) subtype at index review (n = 59).
T A B L E 1 Instrument for scoring clinical outcomes of research for epidermolysis bullosa (iscorEB), maximum score is 138 for clinician score and 120 for self-reported score, with higher score indicating greater severity.